scholarly journals A rush to explore protein–ligand electrostatic interaction energy with Charger

2021 ◽  
Vol 77 (10) ◽  
pp. 1292-1304 ◽  
Author(s):  
Vedran Vuković ◽  
Theo Leduc ◽  
Zoe Jelić-Matošević ◽  
Claude Didierjean ◽  
Frédérique Favier ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Interaction Energy ◽  
Electrostatic Interaction ◽  
Glutathione Transferase ◽  
Multipole Moment ◽  
Point Of View ◽  
Electrostatic Energy ◽  
Electron Densities ◽  
Acta Cryst ◽  
Ligand Interaction

The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524–536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein–ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein–ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.

Fast analytical evaluation of intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density. III. Application to crystal structures via the Ewald and direct summation methods

2020 ◽  
Vol 76 (6) ◽  
pp. 630-651
Author(s):  
Daniel Nguyen ◽  
Piero Macchi ◽  
Anatoliy Volkov
Keyword(s):  
Interaction Energy ◽  
Crystal Structures ◽  
Electron Density ◽  
Small Molecule ◽  
Electrostatic Interaction ◽  
Multipole Moment ◽  
Interaction Energies ◽  
Acta Cryst ◽  
Löwdin Α Function ◽  
Direct Summation

The previously reported exact potential and multipole moment (EP/MM) method for fast and accurate evaluation of the intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density [Volkov, Koritsanszky & Coppens (2004). Chem. Phys. Lett. 391, 170–175; Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536; Nguyen & Volkov (2019). Acta Cryst. A75, 448–464] is extended to the calculation of electrostatic interaction energies in molecular crystals using two newly developed implementations: (i) the Ewald summation (ES), which includes interactions up to the hexadecapolar level and the EP correction to account for short-range electron-density penetration effects, and (ii) the enhanced EP/MM-based direct summation (DS), which at sufficiently large intermolecular separations replaces the atomic multipole moment approximation to the electrostatic energy with that based on the molecular multipole moments. As in the previous study [Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536], the EP electron repulsion integral is evaluated analytically using the Löwdin α-function approach. The resulting techniques, incorporated in the XDPROP module of the software package XD2016, have been tested on several small-molecule crystal systems (benzene, L-dopa, paracetamol, amino acids etc.) and the crystal structure of a 181-atom decapeptide molecule (Z = 4) using electron densities constructed via the University at Buffalo Aspherical Pseudoatom Databank [Volkov, Li, Koritsanszky & Coppens (2004). J. Phys. Chem. A, 108, 4283–4300]. Using a 2015 2.8 GHz Intel Xeon E3-1505M v5 computer processor, a 64-bit implementation of the Löwdin α-function and one of the higher optimization levels in the GNU Fortran compiler, the ES method evaluates the electrostatic interaction energy with a numerical precision of at least 10−5 kJ mol−1 in under 6 s for any of the tested small-molecule crystal structures, and in 48.5 s for the decapeptide structure. The DS approach is competitive in terms of precision and speed with the ES technique only for crystal structures of small molecules that do not carry a large molecular dipole moment. The electron-density penetration effects, correctly accounted for by the two described methods, contribute 28–64% to the total electrostatic interaction energy in the examined systems, and thus cannot be neglected.

Fast analytical evaluation of intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density. I. The Löwdin α-function method

2018 ◽  
Vol 74 (5) ◽  
pp. 524-536 ◽  
Author(s):  
Daniel Nguyen ◽  
Zbigniew Kisiel ◽  
Anatoliy Volkov
Keyword(s):  
Electrostatic Interaction ◽  
Multipole Moment ◽  
Chem Phys ◽  
Processing Unit ◽  
Interaction Energies ◽  
Electron Densities ◽  
Molecular Systems ◽  
Analytical Technique ◽  
Central Processing ◽  
The University

The previously reported [Volkovet al.(2004).Chem. Phys. Lett.391, 170–175] exact potential and multipole moment (EP/MM) method for evaluation of intermolecular electrostatic interaction energies using the nuclei-centered pseudoatom representation of electron densities is significantly improved in terms of both speed and accuracy by replacing the numerical quadrature integration of the exact potential with a fully analytical technique. The resulting approach, incorporated in theXDPROPmodule of the software packageXD, has been tested on several molecular systems ranging in size from water–water to dodecapeptide–dodecapeptide dimers using electron densities constructedviathe University at Buffalo Aspherical Atom Databank. The improved hybrid method provides electrostatic interaction energies within the uncertainty of ≤0.2 kJ mol−1for all benchmark systems. The running time for a dimer of a sizable, 225-atom dodecapeptide is under 4 s on a 2012 central processing unit (2.8 GHz AMD Opteron 6348) and under 3 s on a relatively modern processor (2.8 GHz Intel Xeon E3-1505M v5).

scholarly journals SMPLIP-Score: predicting ligand binding affinity from simple and interpretable on-the-fly interaction fingerprint pattern descriptors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Surendra Kumar ◽  
Mi-hyun Kim
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Scoring Functions ◽  
Binding Affinities ◽  
Ligand Interaction ◽  
Fingerprint Pattern ◽  
Comparable Performance ◽  
Direct Interpretation ◽  
Benchmark Datasets ◽  
Complex Features

AbstractIn drug discovery, rapid and accurate prediction of protein–ligand binding affinities is a pivotal task for lead optimization with acceptable on-target potency as well as pharmacological efficacy. Furthermore, researchers hope for a high correlation between docking score and pose with key interactive residues, although scoring functions as free energy surrogates of protein–ligand complexes have failed to provide collinearity. Recently, various machine learning or deep learning methods have been proposed to overcome the drawbacks of scoring functions. Despite being highly accurate, their featurization process is complex and the meaning of the embedded features cannot directly be interpreted by human recognition without an additional feature analysis. Here, we propose SMPLIP-Score (Substructural Molecular and Protein–Ligand Interaction Pattern Score), a direct interpretable predictor of absolute binding affinity. Our simple featurization embeds the interaction fingerprint pattern on the ligand-binding site environment and molecular fragments of ligands into an input vectorized matrix for learning layers (random forest or deep neural network). Despite their less complex features than other state-of-the-art models, SMPLIP-Score achieved comparable performance, a Pearson’s correlation coefficient up to 0.80, and a root mean square error up to 1.18 in pK units with several benchmark datasets (PDBbind v.2015, Astex Diverse Set, CSAR NRC HiQ, FEP, PDBbind NMR, and CASF-2016). For this model, generality, predictive power, ranking power, and robustness were examined using direct interpretation of feature matrices for specific targets.

scholarly journals Protein-ligand free energies of binding from full-protein DFT calculations: convergence and choice of exchange-correlation functional

2021 ◽  
Author(s):  
Lennart Gundelach ◽  
Christofer S Tautermann ◽  
Thomas Fox ◽  
Chris-Kriton Skylaris
Keyword(s):  
Drug Discovery ◽  
Ligand Binding ◽  
Dft Calculations ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Ligand Interaction ◽  
Exchange Correlation ◽  
Ligand Free ◽  
Protein Ligand Interaction ◽  
Binding Free Energies

The accurate prediction of protein-ligand binding free energies with tractable computational methods has the potential to revolutionize drug discovery. Modeling the protein-ligand interaction at a quantum mechanical level, instead of...

Molecular tapes in the structure of isoguaninium chloride

2017 ◽  
Vol 74 (1) ◽  
pp. 108-112 ◽  
Author(s):  
Urszula Anna Budniak ◽  
Paulina Maria Dominiak
Keyword(s):  
Crystal Structure ◽  
Single Crystal ◽  
Charge Density ◽  
Interaction Energy ◽  
Electrostatic Interaction ◽  
Electrostatic Interactions ◽  
The Other ◽  
X Ray Diffraction ◽  
X Ray ◽  
Diffraction Structure

Isoguanine, an analogue of guanine, is of intrinsic interest as a noncanonical nucleobase. The crystal structure of isoguaninium chloride (systematic name: 6-amino-2-oxo-1H,7H-purin-3-ium chloride), C5H6N5O+·Cl−, has been determined by single-crystal X-ray diffraction. Structure analysis was supported by electrostatic interaction energy (E es) calculations based on charge density reconstructed with the UBDB databank. In the structure, two kinds of molecular tapes are observed, one parallel to (010) and the other parallel to (50\overline{4}). The tapes are formed by dimers of isoguaninium cations interacting with chloride anions. E es analysis indicates that cations in one kind of tape are oriented so as to minimize repulsive electrostatic interactions.

scholarly journals Biophysical and functional characterization of Norrin signaling through Frizzled4

2018 ◽  
Vol 115 (35) ◽  
pp. 8787-8792 ◽  
Author(s):  
Injin Bang ◽  
Hee Ryung Kim ◽  
Andrew H. Beaven ◽  
Jinuk Kim ◽  
Seung-Bum Ko ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Wnt Signaling ◽  
Conformational Changes ◽  
Cellular Response ◽  
Transmembrane Domain ◽  
Functional Characterization ◽  
Intracellular Loop ◽  
Ligand Interaction ◽  
Rich Domain ◽  
Linker Domain

Wnt signaling is initiated by Wnt ligand binding to the extracellular ligand binding domain, called the cysteine-rich domain (CRD), of a Frizzled (Fzd) receptor. Norrin, an atypical Fzd ligand, specifically interacts with Fzd4 to activate β-catenin–dependent canonical Wnt signaling. Much of the molecular basis that confers Norrin selectivity in binding to Fzd4 was revealed through the structural study of the Fzd4CRD–Norrin complex. However, how the ligand interaction, seemingly localized at the CRD, is transmitted across full-length Fzd4 to the cytoplasm remains largely unknown. Here, we show that a flexible linker domain, which connects the CRD to the transmembrane domain, plays an important role in Norrin signaling. The linker domain directly contributes to the high-affinity interaction between Fzd4 and Norrin as shown by ∼10-fold higher binding affinity of Fzd4CRD to Norrin in the presence of the linker. Swapping the Fzd4 linker with the Fzd5 linker resulted in the loss of Norrin signaling, suggesting the importance of the linker in ligand-specific cellular response. In addition, structural dynamics of Fzd4 associated with Norrin binding investigated by hydrogen/deuterium exchange MS revealed Norrin-induced conformational changes on the linker domain and the intracellular loop 3 (ICL3) region of Fzd4. Cell-based functional assays showed that linker deletion, L430A and L433A mutations at ICL3, and C-terminal tail truncation displayed reduced β-catenin–dependent signaling activity, indicating the functional significance of these sites. Together, our results provide functional and biochemical dissection of Fzd4 in Norrin signaling.

scholarly journals Crystal structures and Hirshfeld surface analyses of (E)-N′-benzylidene-2-oxo-2H-chromene-3-carbohydrazide and the disordered hemi-DMSO solvate of (E)-2-oxo-N′-(3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide: lattice energy and intermolecular interaction energy calculations for the former. Corrigendum

2019 ◽  
Vol 75 (12) ◽  
pp. 1952-1952
Author(s):  
Ligia R. Gomes ◽  
John Nicolson Low ◽  
James L. Wardell ◽  
Camila Capelini ◽  
José Daniel Figueroa Villar ◽  
...  
Keyword(s):  
Interaction Energy ◽  
Crystal Structures ◽  
Intermolecular Interaction ◽  
Lattice Energy ◽  
Hirshfeld Surface ◽  
Intermolecular Interaction Energy ◽  
Acta Cryst ◽  
Energy Calculations

In the paper by Gomes et al. [Acta Cryst. (2019), E75, 1403–1410], there was an error and omission in the author and affiliation list.

Active GPIIb-IIIa conformations that link ligand interaction with cytoskeletal reorganization

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2487-2495 ◽  
Author(s):  
Traci Heath Mondoro ◽  
Melanie McCabe White ◽  
Lisa K. Jennings
Keyword(s):  
Platelet Aggregation ◽  
Ligand Binding ◽  
Critical Role ◽  
Adenosine Diphosphate ◽  
Full Scale ◽  
Cytoskeletal Reorganization ◽  
Clot Retraction ◽  
Ligand Interaction ◽  
High Affinity ◽  
Combination Treatments

Abstract Glycoprotein (GP) IIb-IIIa plays a critical role in platelet aggregation and platelet-mediated clot retraction. This study examined the intramolecular relationship between GPIIb-IIIa activation and fibrinogen binding, platelet aggregation, and platelet-mediated clot retraction. To distinguish between different high-affinity activation states of GPIIb-IIIa, the properties of an antibody (D3) specific for GPIIIa that induces GPIIb-IIIa binding to adhesive protein molecules and yet completely inhibits clot retraction were used. Clot retraction inhibition by D3 was not due to altered platelet-fibrin interaction; however, combination treatments of D3 and adenosine diphosphate (ADP) inhibited full-scale aggregation and decreased the amounts of GPIIb-IIIa and talin incorporated into the core cytoskeletons. Morphologic evaluation of the D3/ADP aggregates showed platelets that were activated but to a lesser extent when compared to ADP only. ADP addition to platelets caused an increase in the number of D3 binding sites indicating that ligand had bound to the GPIIb-IIIa receptor. These data suggest that high-affinity GPIIb-IIIa– mediated ligand binding can be separated mechanistically from GPIIb-IIIa–mediated clot retraction and that clot retraction requires additional signaling through GPIIb-IIIa after ligand binding. The conformation recognized by D3 represents the expression of a GPIIb-IIIa activation state that participates in full-scale platelet aggregation, cytoskeletal reorganization, and clot retraction.

Improved ligand-binding- and signaling-competent human NK2R yields in yeast using a chimera with the rat NK2R C-terminus enable NK2R-G protein signaling platform

2019 ◽  
Vol 32 (10) ◽  
pp. 459-469 ◽  
Author(s):  
Abhinav R Jain ◽  
Zachary T Britton ◽  
Chester E Markwalter ◽  
Anne S Robinson
Keyword(s):  
Protein Engineering ◽  
Ligand Binding ◽  
G Protein ◽  
Mammalian Cells ◽  
Protein Signaling ◽  
Ligand Interaction ◽  
Downstream Signaling ◽  
Drug Candidates ◽  
C Terminus ◽  
Engineering Strategy

Abstract The tachykinin 2 receptor (NK2R) plays critical roles in gastrointestinal, respiratory and mental disorders and is a well-recognized target for therapeutic intervention. To date, therapeutics targeting NK2R have failed to meet regulatory agency approval due in large part to the limited characterization of the receptor-ligand interaction and downstream signaling. Herein, we report a protein engineering strategy to improve ligand-binding- and signaling-competent human NK2R that enables a yeast-based NK2R signaling platform by creating chimeras utilizing sequences from rat NK2R. We demonstrate that NK2R chimeras incorporating the rat NK2R C-terminus exhibited improved ligand-binding yields and downstream signaling in engineered yeast strains and mammalian cells, where observed yields were better than 4-fold over wild type. This work builds on our previous studies that suggest exchanging the C-termini of related and well-expressed family members may be a general protein engineering strategy to overcome limitations to ligand-binding and signaling-competent G protein-coupled receptor yields in yeast. We expect these efforts to result in NK2R drug candidates with better characterized signaling properties.

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